ETHANOL EFFECTS ON GLYCINE RECEPTOR/CHANNEL FUNCTION

乙醇是一种有效的脑抑制药，也是一种添加剂药物。 新的证据表明，甘氨酸受体/通道(GlyRs)是 对药理上相关的乙醇浓度敏感。自.以来 甘氨酸抑制神经元活动，增强GlyR功能将 有望增强神经元抑制，并可能有助于 乙醇的神经元抑制作用。因此，我们建议研究 乙醇对甘氨酸诱导的多巴胺能神经元反应的影响 来自大脑腹侧被盖区(VTA)的奖赏中心 因为滥用药物。这项研究的总体目标是调查 乙醇改变GlyR功能的作用机制 体内酒精对中枢神经系统(CNS)的影响。至 为了实现这一目标，将检验以下三个假设。 假设一是乙醇与GlyR相互作用。Etoh调节 改变GlyRs功能对多巴胺能神经元兴奋性的影响 假设II是乙醇与GlyR的相互作用受 细胞内GlyR的蛋白质磷酸化状态 PKA、PKC和G蛋白的活性。假设III是GlyR 多巴胺能神经元的结构、细胞内C_1浓度以及 因此，甘氨酸诱导的反应及其对乙醇的反应 与时俱进。这些假说将在VTA神经元上进行测试 新鲜从新生和成年大鼠身上分离出来的。全细胞贴片- 钳夹技术(尤其是穿孔补片技术)将 用于记录甘氨酸诱导的反应，包括膜电流， 无电和无电时自发放电的电位和变化 艾托的存在。蛋白激酶的特异性激活剂和抑制物 将使用A和C以及G-蛋白来识别酶途径 涉及乙醇对GlyRs的任何影响。这些研究将 显著提高了我们对乙醇对中枢神经系统影响的理解 在分子和细胞水平上的GlyRs。更好地了解 乙醇在大脑中的作用将提高我们对相关的理解 强化机制，这将反过来促进 确定可能在治疗中有价值的策略 酗酒和胎儿酒精综合症。

Ethanol (EtOH) is an effective brain depressant and an additive drug. Emerging evidence suggests that glycine receptor/channels (GlyRs) are sensitive to pharmacologically relevant concentrations of EtOH. Since glycine inhibits neuronal activity, potentiation of GlyR function would be expected to enhance neuronal inhibition and perhaps contribute to the neuronal depressant effects of EtOH. Therefore, we propose to examine the effects of EtOH on glycine-induced responses of dopaminergic neurons from the ventral tegmental area (VTA) of the brain, the reward center for drug abuse. The overall objective of this study is to investigate the mechanisms by which EtOH alteration of GlyR function contributes to the central nervous system (CNS) consequences of alcohol in vivo. To achieve this objective the following three hypotheses will be tested. HYPOTHESIS I is that EtOH interacts with the GlyR. EtOH regulates the excitability of dopaminergic neurons by altering functions of GlyRs. HYPOTHESIS II is that EtOH interactions with the GlyR are modulated by the protein phosphorylation status of the GlyR, the intracellular activity of PKA, PKC and G-proteins. HYPOTHESIS III is that GlyR structure, intracellular C1-concentration of dopaminergic neurons and, consequently, glycine-induced responses and their response to EtOH change with development. These hypotheses will be tested on VTA neurons freshly isolated from both neonatal and mature rats. Whole-cell patch- clamp technique (especially gramicidin perforated patch technique) will be used to record glycine-induced responses, including membrane current, potential and the alteration of spontaneous firing in the absence and presence of EtOH. Specific activators and inhibitors of protein kinases A and C and of G-proteins will be used to identify the enzyme pathways involved in any effects, of EtOH on GlyRs. These studies will significantly advance our understanding of the effects of EtOH on CNS GlyRs at the molecular and cellular levels. A better knowledge of the actions of EtOH in the brain will improve our understanding of related reinforcement mechanisms, which will, in turn, facilitate the identification of strategies which might be of value in the treatment of alcohol abuse and fetal alcohol syndrome.